AstraZeneca showcases next-generation Oncology pipeline addressing unmet patient needs at AACR Annual Meeting

Presentations highlight new Immuno-Oncology and DNA Damage Response targets, expanding beyond checkpoint and PARP inhibition

AstraZeneca will share pioneering research and development across its successful Oncology portfolio and extensive next-generation pipeline at the American Association for Cancer Research (AACR) Annual Meeting in Atlanta, USA, 29 March to 3 April 2019.

The new research will showcase AstraZeneca’s potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, taking the DNA Damage Response (DDR) pipeline beyond PARP inhibition. Additional highlights include new insights from the MYSTIC and TATTON trials for Imfinzi (durvalumab) and Tagrisso (osimertinib) in predicting response and addressing treatment resistance in lung cancer.

In total, data from 84 presentations will illustrate the progress of AstraZeneca’s Oncology pipeline, with 28 abstracts reporting new Immuno-Oncology (IO) data, 33 focused on complementary biological pathways exploring the DDR mechanism, and 20 on tumour drivers and resistance mechanisms.

José Baselga, Executive Vice President, Research & Development, Oncology, said: “AstraZeneca is continuing to strengthen its portfolio of innovative cancer medicines by exploring new indications and developing a pioneering next-generation pipeline. We will be sharing some of our latest research at the 2019 AACR Annual Meeting, including 28 new molecular entities and six combinations, highlighting an exciting new phase of scientific discovery from our Oncology R&D.”

IO pipeline explores new pathways to enhance immune response

Key data from AstraZeneca’s early-stage clinical and preclinical IO pipeline include potential new medicines targeting multiple pathways, providing insight into novel mechanisms to boost current immune response and modify the tumour microenvironment both alone and in combination with checkpoint inhibition.

Presentations will highlight AstraZeneca’s growing portfolio in small molecules and antisense oligonucleotides (ASOs) targeting immunosuppressive mechanisms in cancer, and the Company’s exploration of the adenosine pathway, which is increasingly recognised as critical to tumour suppression and represents a new frontier within IO.

  • Phase I and preclinical data demonstrating AZD4635, a small molecule A2AR antagonist, prevents adenosine-mediated immunosuppression. Early clinical activity has been observed with AZD4635 monotherapy or in combination with Imfinzi in patients with metastatic castration-resistant prostate cancer (Abstracts #LB-192/10, #CT026/21)
  • Preclinical research on the activity of ASO AZD8701 (ION-AZ7), showing that inhibiting FOXP3 may limit immunosuppressive functions and induce tumour regression (Abstract #2713)
  • Preclinical pharmacodynamic and mechanistic data illustrating how danvatirsen (AZD9150), a STAT3 ASO reverses immunosuppression to produce significant anti-tumour effects, both as monotherapy and in combination with anti-PDL1 (Abstract #3215/25)
  • Preclinical data for MEDI5083, a novel fusion protein which activates the CD40 pathway, indicating robust immune activation and anti-tumour activity (Abstract #1534/3)
  • Preclinical data for MEDI1191, a novel IL12-based treatment designed for injection directly into tumours, showing potential to drive anti-tumour response for patients with solid tumours both as monotherapy and in combination with anti-PDL1 (Abstract #5017/11)

Next wave of DDR targets

New research will showcase AstraZeneca’s DDR pipeline beyond PARP inhibition, including on the discovery and first structural disclosure of AZD7648, a potent and selective DNA-PK inhibitor (Abstract #DDT01-02). DNA-PK is critical in repairing DNA double strand breaks through the non-homologous end joining (NHEJ) pathway and has also been linked to the replication stress response (RSR), a type of DDR.

Additional new data will be shared on reversing PARP inhibitor resistance by targeting alternative DDR dependencies, like the RSR (Abstract #932).

Predicting response and addressing treatment resistance in lung cancer: new insights from MYSTIC and TATTON trials for Imfinzi and Tagrisso

Exploratory analyses of blood and tissue tumour mutational burden (TMB) from the Phase III MYSTIC trial assess TMB as a potential biomarker of survival in 1st-line use of Imfinzi with or without tremelimumab vs. chemotherapy in metastatic non-small cell lung cancer (NSCLC) (Abstract #CT074). The trial did not meet the primary endpoints, but Imfinzi monotherapy demonstrated clinical activity in the primary analysis. The MYSTIC trial provides the most comprehensive data set to date evaluating blood TMB and is the only Phase III randomised, controlled trial to demonstrate an association between high TMB and overall survival benefit with immunotherapy treatment. This new analysis will further evaluate the use of TMB as a potential biomarker predictive of survival benefit with IO treatment.

In addition, several abstracts will be presented from the TATTON Phase Ib trial testing the combination of Tagrisso with potential new medicines savolitinib or selumetinib in NSCLC patients who have progressed on prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment (Abstracts #CT032, #CT033, #CT034). The TATTON trial supports SAVANNAH, an ongoing Phase II clinical trial exploring the combination of Tagrisso and savolitinib to overcome MET-driven EGFR-TKI resistance following treatment with Tagrisso in EGFR-mutated (EGFRm) NSCLC. Characterisation of detection methods for identifying MET-driven EGFR-TKI resistance will be presented (Abstract #4897/20). TATTON will also inform the trial design of ORCHARD, a Phase II platform trial exploring potential new treatment options to address resistance mechanisms in patients with EGFRm NSCLC who have experienced disease progression following 1st-line treatment with Tagrisso.

Key AstraZeneca presentations at AACR 2019 

Lead author Abstract title Presentation details
Immuno-Oncology
Peters, S  Tumour mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): blood and tissue TMB analysis from MYSTIC, a Phase 3 study of first-line durvalumab ± tremelimumab vs chemotherapy Abstract #CT074Session CTPL03 - Optimizing PD-1/PD-L1 Immune Checkpoint Inhibitor Therapy: Dedicated to the Memory of Waun Ki HongMonday 1 April10:30am-12:45pmMarcus Auditorium- Bldg A-GWCC
Srinivasan, S STAT3 ASO reverses immunosuppression and enhances cytotoxic cell function to enhance PDL1 blockade Abstract #3215/25Session PO.IM02.01 - Combination Immunotherapies 2Tuesday 2 April8:00am-12:00pmSection 23
Barbon, CM The A2AR antagonist AZD4635 prevents adenosine-mediated immunosuppression of CD103+ dendritic cells Abstract #LB-192/10Session LBPO.IM02 - Late-Breaking Research:
Immunology 2
Tuesday 2 April8:00am-12:00pmSection 42
Merchant, MS Evidence of Immune Activation in the first-in-human Phase 1a dose escalation study of the Adenosine 2a Receptor Antagonist, AZD4635, in patients with advanced solid tumors Abstract #CT026/21Session PO.CT01 - Phase I Clinical Trials: Part 1Sunday 31 March1:00pm-5:00pmSection 16
Sinclair, C Discovery and characterization of AZD8701, a high affinity antisense oligonucleotide targeting FOXP3 to relieve immunosuppression in cancer Abstract #2713Session MS.IM02.01 - Rational Combinations of ImmunotherapyMonday 1 April4:35pm-4:50pmRoom A411-Georgia World CC
Wang, Y MEDI5083, a novel CD40L-Fc fusion protein, activates the CD40 pathway on antigen presenting cells and promotes a robust anti-tumor immune response in a B16F10 murine tumor model Abstract #1534/3Session PO.IM02.17 - Therapeutic Antibodies 2Monday 1 April8:00am-12:00pmSection 25
Luheshi, N MEDI1191, a novel IL-12 mRNA therapy for intratumoral injection to promote TH1 transformation of the patient tumor microenvironment Abstract #5017/11Session PO.IM02.10 - Tumor Immune MicroenvironmentWednesday 3 April 8:00am-12:00pmSection 25
DNA damage response
Goldberg, FW Discovery and first structural disclosure of AZD7648, a potent and selective DNA-PK inhibitor Abstract #DDT01-02Session DDT01 - New Drugs on the Horizon: Part 1Sunday 31 March1:24pm-1:48pmRoom A305 - Georgia World CC
Cadogan, EB AZD7648: A potent and selective inhibitor of DNA-PK with pharmacodynamic and monotherapy anti-tumour activity Abstract #3505/16Session PO.MCB07.03 - DNA Damage and Repair 3Tuesday 2 April8:00am-12:00pmSection 35
Fok, J AZD7648, a potent and selective inhibitor of DNA-PK, potentiates the activity of ionising radiation and doxorubicin in vitro and causes tumour regression in xenograft models Abstract #3512/23Session PO.MCB07.03 - DNA Damage and Repair 3Tuesday 2 April8:00am-12:00pmSection 35
O’Connor, M Reversing PARP inhibitor resistance by targeting the replication stress response Abstract #932Session MS.ET03.01 - Drug ResistanceSunday 31 March4:35pm-4:50pmRoom B304 - Georgia World CC
Tumour drivers and resistance
Yu, H TATTON Phase Ib expansion cohort: osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET amplified NSCLC after progression on prior first/second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) Abstract #CT032Session CTPL02 - Can the Challenge of NSCLC Resistance be MET or Will We Not MEK It?Sunday 31 March3:00pm-5:15pm Marcus Auditorium- Bldg A-GWCC
Sequist, L TATTON Phase Ib expansion cohort: osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET-amplified NSCLC after progression on prior third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) Abstract #CT033Session Clinical Trials Plenary, Can the Challenge of NSCLC Resistance be MET or Will We Not MEK it?Sunday 31 March3:00pm-5:15pm Marcus Auditorium- Bldg A-GWCC
Ramalingam, S Osimertinib plus selumetinib for patients (pts) with EGFR-mutant (EGFRm) NSCLC following disease progression on an EGFR-TKI: results from the Phase Ib TATTON study Abstract #CT034 Session Clinical Trials Plenary, Can the Challenge of NSCLC Resistance be MET or Will We Not MEK it?Sunday 31 March3:00pm-5:15pmMarcus Auditorium- Bldg A-GWCC
Hartmaier, RJ Detection of MET-mediated EGFR tyrosine kinase inhibitor (TKI) resistance in advanced non-small cell lung cancer (NSCLC): biomarker analysis of the TATTON study Abstract #4897/20Session PO.CL11.07 - Novel Strategies for Biomarker Identification and Use in Cancer 3Wednesday 3 April8:00am-12:00pmSection 19
Liquid biopsies
Barrett, JC  Regulatory Considerations for Utilizing Liquid Biopsies in Drug and Diagnostic Development  Major Symposium: Regulatory Science and PolicySession SYPOL07 - Regulatory Considerations for Utilizing Liquid Biopsies in Drug and Diagnostic DevelopmentTuesday 2 April3:00pm-5:00pmRoom A402 - Georgia World CC

- Ends -

 
Notes to editors

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

About AstraZeneca

AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit astrazeneca.com and follow us on Twitter @AstraZeneca.

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